Inverse chromatography methods and apparatus for evaluation of interactions between modifying agents and receptors comprising fabric materials, foodstuff materials and other materials

ABSTRACT

Methods and apparatus for the evaluation of interactions between substances using inverse chromatography are disclosed. Preferably, interactions are evaluated between a liquid test sample and a solid phase comprising a receptor in the presence of a liquid carrier. Preferably, one of the modifying agent or receptor are members of a combinatorial library.

[0001] This application is related to, and claims priority under 35U.S.C. Sec. 119(e) to co-owned, co-pending U.S. provisional applicationSer. No. 60/300,589 entitled “Evaluation of Interactions BetweenSubstances” filed Jun. 22, 2001 by Petro et al.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to the evaluation of interactions betweensubstances using inverse chromatography methods and apparatus. The term“substance” is used herein, i.e. throughout this specification, to meana single element or compound, or a mixture of elements and/or compounds.The invention is particularly (but not exclusively) useful in the fieldof combinatorial science.

[0004] 2. Introduction to the Invention

[0005] In the field of combinatorial science, there is a continuing needfor improved methods for characterizing the members of libraries ofsubstances.

[0006] The techniques of chromatography are well-known. In one widelyused technique, often referred to as liquid solid chromatography, aliquid carrier (the “mobile phase”) is passed over a solid (the“stationary phase”) in a column. A sample is injected into the mobilephase before the mobile phase enters the column. The sample comprises atleast one substance which interacts with the solid. The rate at whichthe substance migrates through the column depends on its relativeaffinity for the mobile and stationary phases. The technique can be usedto separate two substances with different relative affinities for thephases, to characterize an unknown sample (using one or more knownsolids), or (in the process sometimes referred to as inversechromatography) to characterize a known solid (using one or more knownsamples). Reference may made for example to U.S. Pat. No. 4,869,093(Gilbert); J. Liquid Chromatography, 3 (3), (1983), 403-417, Schram etal.; Org. Geochem. (1989), 14 (2), 157-164,Antworth et al;Chromatographia 36 (1993), 259-262, Jerebak et al.; Sekitan Kagaku KaigiHappyo Ronbunshu (1993), 30th, 122-125 (Morino et al.); Conf. Proc. Int.Conf. Coal Sci, 7th (1993, 1, 419-422, Takanohashi et al.; Energy Fuels(1996), 10 (4), 1012-1016, Morino et al.; Energy Fuels (1996), 10 (4),1017-1021, Kaneko et al.; Anal. Biochem. 242 (1996), 104-111; Brissovaet al; and Reactive Polymers 23 (1994), 173-182 Petro et al. Referencemay also be made to U.S. Pat. Nos. 6,175,409, 6,406,632, 6,265,226,6,260,407, 6,294,388 and PCT Publication WO 99/51980. The entiredisclosure of each of the patents, publications and patent applicationsreferred to above is incorporated herein by reference for all purposes.

SUMMARY OF INVENTION

[0007] This invention relates to methods and apparatus which are usefulfor evaluating the interaction between a receptor and a modifying agentin the presence of a liquid carrier, and which make use of novel andinventive variations of the known techniques of liquid solidchromatography. In the terminology often used in chromatography, theinvention includes (but is not limited to) methods in which the receptoris the probe and the modifying agent is the sample, and methods in whichthe modifying agent is the probe and the receptor is the sample.

[0008] In a first aspect of the invention, one of the receptor,modifying agent and liquid carrier is a member of a library, preferablyeither the receptor or modifying agent is a member of a library, and ineither case, the method includes evaluating members of the library in anumber of test procedures, and using the results of test procedures toselect at least one substance for further testing. The substanceselected for further testing will generally be a member of the library,but may be a substance having a known relationship to a member of thelibrary.

[0009] In other aspects, the invention provides various methods whichare useful as test procedures in the first aspect of the invention, butwhich are also useful in other contexts, for example for evaluation ofinteraction between substances by inverse chromatography, and for therapid testing of a sample withdrawn from a continuous process. In yetfurther aspects, the invention provides apparatus suitable for carryingout the methods of the invention.

[0010] The term “evaluating” is used herein in a broad sense to denoteany useful assessment of the interaction between the receptor and themodifying agent. For example, in the first aspect of the invention, theterm includes any assessment which makes it possible to select at leastone substance for further testing. The term “receptor” is used herein todenote a substance which can form at least part of a solid phase. Thus,the receptor, alone or in combination with a solid, correspondsgenerally to the stationary phase in conventional liquid solidchromatography. The term “liquid carrier” is used herein to denote anyliquid which can be passed continuously over the solid comprising thereceptor while the solid is confined in a test chamber. Thus, the liquidcarrier corresponds generally to the mobile phase in conventional liquidsolid chromatography. The term “modifying agent” is used herein todenote a substance which can form at least part of a liquid sample whichcan be injected into a stream of the liquid carrier before the stream ispassed over the solid in the test chamber. The term “library” is usedherein in a broad sense to denote a plurality of identified substances,typically an associated collection of identified substances. The libraryis preferably a spatially determinate array of identified substancesformed at or in or situated on a common substrate. Preferably, but notnecessarily, the members of the library differ from each other in somesystematic way, so that the variation of the results of the testprocedures can be correlated with those differences. For example, themembers can differ from each other in one or more quantified ways. Suchdifferences can be quantified by measurements carried out duringpreparation of the substances, or by measurements carried out on thesubstances themselves. The differences can be ascertained before orafter members of the library have been selected in accordance with thepresent invention.

[0011] The method of the first aspect of the invention comprisesconducting a plurality of test procedures, each of the test procedurescomprising the steps of

[0012] (a) injecting a liquid test sample comprising the modifying agentinto a stream of the liquid carrier, the injection being carried outover a limited time so that a distinct test section of the streamcontains the test sample;

[0013] (b) passing the stream of liquid carrier containing the testsample over a solid phase in a test chamber, the solid phase comprisingthe receptor; and

[0014] (c) examining the stream of liquid carrier leaving the testchamber to ascertain a variable which reflects the interaction of themodifying agent and the receptor in the presence of the liquid carrier.

[0015] Step (c) of the method will often comprise examining a distinctevaluation section of the stream corresponding to the test section inorder to ascertain a property of the modifying agent. The term “toascertain a property of the modifying agent” is used herein to includeascertaining a property of the modifying agent itself and/orascertaining a property of a substance which is produced by theinteraction of the modifying agent and the receptor and/or ascertaininga property of part only of the modifying agent.

[0016] The results obtained in the steps (c) of the test procedures canoptionally be used to select at least one substance for further testing.The further testing can for example involve the interaction between (i)a selected member or members of the library and (ii) the other two ofthe receptor, modifying agent and liquid carrier used in the testprocedures. The further testing can otherwise be unrelated to theoriginal evaluation.

[0017] The term “examining the stream of liquid carrier leaving the testchamber to ascertain a variable which reflects the interaction of themodifying agent and the receptor in the presence of the liquid carrier”is used herein in a broad sense to denote any examination which enablesthe desired evaluation to be made. For example, as further explainedbelow, it may be sufficient to compare the results of the testprocedures without quantifying any property of the modifying agent.Preferably (but not necessarily) step (c), alone or in combination withother steps, makes it possible to calculate the proportion of themodifying agent, or a component of the modifying agent, retained in thetest chamber.

[0018] The objective of the known chromatographic procedures is (i) toachieve at least some separation of the individual components of thesample, followed by collection of at least one separated product, and/or(ii) to achieve a substantial degree of equilibration between the sampleand the stationary phase in order to provide detailed characterizingdata. The known procedures use, therefore, combinations of stationaryand mobile phases, processing times, and columns which achieve theseobjectives. By contrast, it is not an objective of the present inventionto recover a separated product or to achieve equilibrium between thesample and the solid phase. Furthermore, in the first aspect of theinvention, the library is preferably examined as quickly as isconsistent with selection of a limited number of members for furthertesting and under dynamic conditions which simulate an ultimate end-use.For example, the objective might be to identify the members of a libraryhaving the potential to be additives which produce a desired effect on afabric being laundered or dry cleaned, or on photographic film beingdeveloped, or in a paint being applied to a building material.

[0019] Because of these differences in objectives, the test proceduresused in the first aspect of the invention often have at least one (i.e.one or more) of the following characteristics which distinguish themfrom known chromatographic procedures.

[0020] (I) The receptor is a substance which has not been used as thestationary phase in liquid solid chromatography. For example, thereceptor comprises

[0021] (1) a fabric,

[0022] (2) at least 50% by weight of particles having an aspect ratio ofat least 2 and at least one dimension which is greater than 100 micron,

[0023] (3) a substantially pore-free sheet of an organic polymer,

[0024] (4) a foodstuff,

[0025] (5) a natural or artificial mammalian tissue,

[0026] (6) a polysaccharide, a protein or a nucleic acid,

[0027] (7) a catalyst,

[0028] (8) an elemental metal or metal alloy,

[0029] (9) wood,

[0030] (10) concrete,

[0031] (11) natural or artificial stone,

[0032] (12) a semiconductor substance, or

[0033] (13) a DNA chip, a molecular recognition chip, or a separationchip. The receptor material preferably includes mammalian tissue, eitherartificial or natural. Other preferred receptor materials are selectedfrom the group consisting of a fabric, a substantially pore-free sheetof an organic polymer, a foodstuff, wood, concrete, natural orartificial stone, and a semiconductor substance. Within this group,receptor materials selected from a fabric, a foodstuff and asemiconductor substance are particularly preferred.

[0034] (II) The test chamber is less efficient than columns used inliquid solid chromatography. For example, the efficiency of the testchamber is less than 80, preferably less than 50, particularly less than10, theoretical plates.

[0035] (III) The test procedures are carried out rapidly and underdynamic conditions. These dynamic conditions are not intended to promoteseparation of the modifying agent into component parts or to ensure thatall of the modifying agent passes through the test chamber. Furthermore,the extent of the interaction between the receptor and the modifyingagent can vary widely in the different test procedures. As a result, oneor more of the following conditions are often fulfilled.

[0036] (1) In each of the test procedures, the test sample comprises aninitial quantity of the modifying agent, and in at least one of the testprocedures at least 1%, often at least 10%, e.g. 20-70% or 30-50%, ofthe initial quantity of the modifying agent is retained in the testchamber. Substantially all of the modifying agent retained until the endof a test procedure remains retained on the solid phase duringsubsequent test procedures, and thus can be regarded as beingirreversibly retained on the solid phase under the test conditions.

[0037] (2) In each of the test procedures, the test sample comprises aninitial quantity of the modifying agent, and the difference between (i)the lowest percentage of the initial quantity of modifying agentretained in the test chamber in any of the test procedures and (ii) thehighest percentage of the initial quantity of modifying agent retainedin the test chamber in any of the test procedures, is at least 10, forexample 10-70, often at least 25, for example 30-60.

[0038] (3) In at least one, preferably in each, of the test procedures,the receptor is not saturated by the modifying agent. The extent towhich saturation is being approached can be assessed by repeating one ofthe test procedures. Preferably, in such a repeated test procedure, thesame proportion of the modifying agent is retained by the receptor,indicating that the receptor is far from saturation. If a lesserproportion is retained, this indicates that the receptor is approachingsaturation; and when none of the modifying agent is retained, thereceptor is saturated.

[0039] (4) In at least one, preferably in each, of the test procedures,a plot of time against concentration of the modifying agent in thestream of liquid carrier leaving the test chamber has only a singlepeak, with the slope of the plot being positive at all points on oneside of the peak and negative at all points on the other side of thepeak.

[0040] (5) In at least one, preferably in each, of the test procedures,the stream of liquid leaving the test chamber is passed through adetector, and the time taken for the evaluation section to pass throughthe detector is less than five times the time taken for the test sectioncontaining the modifying agent to pass through the entrance to the testchamber.

[0041] (IV) The desired evaluation is carried out merely by ascertainingthe proportion of the modifying agent which is retained in the testchamber (i.e. it is unnecessary to know, in absolute terms, the quantityof modifying agent initially present in the sample). This makes itpossible to carry out the desired evaluation by comparing (a) theresults of passing the sample-carrying liquid stream through the testchamber and (b) the results of a reference procedure in which a similarsample-carrying liquid stream is passed through a reference chamberwhich (i) is free of any substance which interacts with the modifyingagent, or (ii) contains a known solid substance. In some cases,satisfactory results can be obtained by comparing the results of each ofthe test procedures with a single reference procedure or with two ormore reference procedures which are carried out at appropriateintervals. However, this requires a uniformity between the differentprocedures which is not always easy to attain. It is preferred,therefore, that each of the test procedures should itself incorporatethe reference procedure. In this case, each of the test proceduresfurther comprises

[0042] (d) injecting a liquid reference sample into a second stream ofthe liquid carrier, the composition of the second sample beingsubstantially identical to the composition of the test sample, and theinjection being carried out over a limited time so that only a distinctreference section of the stream contains the reference sample;

[0043] (e) passing the second stream of liquid carrier containing thereference sample through a reference chamber which is free of anysubstance which interacts with the modifying agent;

[0044] (f) examining the stream of liquid carrier leaving the referencechamber to ascertain a property of the modifying agent remaining in thestream; and

[0045] (g) comparing the results obtained in steps (c) and (f) toevaluate the interaction between the receptor and the modifying agent.

[0046] In the aforementioned protocol, the second stream into which thereference sample is injected can be the same stream into which the testsample was injected (or alternatively, can be a separate and independentstream (i.e., a separate line)). Preferably, therefore, the first liquidstream containing the test section and second liquid stream containingthe reference section are obtained by

[0047] (i) injecting into the stream of liquid carrier a liquid unitwhose composition is the same as the composition of the test andevaluation samples and whose size is equal to the sum of the sizes ofthe test and evaluation samples, the injection being carried out over alimited time so that only a distinct section of the liquid streamcontains the liquid unit, and

[0048] (ii) splitting the liquid stream containing the liquid unit intoa first sub-stream which passes through the test chamber and includesthe test section and a second sub-stream which passes through thereference chamber and includes the reference section.

[0049] In the methods of the first aspect of the invention, the testprocedures can be carried out in series or in parallel or both.

[0050] In some embodiments, it is particularly preferably to useparallel (simultaneous) procedures, especially with respect toapplications in combinatorial materials science, in which either thelibrary or receptors are members of a combinatorial library comprisingat least four members, such that members are evaluated for interactionbetween a receptor member of the combinatorial library and a modifyingagent, or alternatively for interaction between a modifying agent memberof a combinatorial library and a receptor, in each case in the presenceof a liquid carrier. Preferably each of the at least four members of thecombinatorial library comprise a different non-biological polymer. Themethod includes conducting at least four test procedures in parallelunder a common set of test conditions, with the receptor, modifyingagent and liquid carrier being the same in each of the test proceduresexcept that in each test procedure a different member of thecombinatorial library is used.

[0051] The parallel testing/evaluation can include multiple flowchannels with simultaneous contacting of test samples (comprising amodifying agent ) and solid phases (comprising a receptor) as comparedbetween different channels. The injection into such parallel-configuredcarrier streams, each having its own dedicated test chamber, can beaccomplished in a sequential manner, as described for example inco-owned U.S. Pat. No. 6,296,771. Alternatively, the injection into suchparallel-configured carrier streams can also be accomplished inparallel, using parallel injection systems such as are disclosed inco-owned, co-pending U.S. applications, Ser. No. 09/641,442 filed Aug.2, 2002 by Freitag et al. and Ser. No. 10/092,035 filed Mar. 6, 2002 byBergh et al. In either case, the detection (examining step) ispreferably done in parallel, but can also be sequential. In a preferredprotocol, the at least four parallel test procedures can comprise:

[0052] (a) simultaneously injecting at least four liquid test samplescomprising an initial quantity of the modifying agent into at least fourseparate and distinct streams of the liquid carrier, respectively, theinjections being carried out over a limited time so that distinct testsections of the at least four streams contain the test sample,

[0053] (b) simultaneously passing the at least four streams of liquidcarrier containing the test samples over a solid phase in at least fourseparate and distinct test chambers, respectively, the solid phasecomprising the receptor,

[0054] (c) retaining at least 10% of the initial quantity of themodifying agents on the solid phase in each of the at least four testchambers, the retained modifying agents being irreversibly retainedunder the test conditions of the procedures, and

[0055] (d) simultaneously examining the at least four streams of liquidcarrier leaving the test chamber to ascertain, for each of the at leastfour streams, a variable which reflects the interaction of the modifyingagent and the receptor in the presence of the liquid carrier for thatrespective stream, and

[0056] (e) comparing the interaction of the modifying agent and thereceptor for each of the at least four streams to determine a relativeranking of the members of the combinatorial library with respect to suchinteraction.

[0057] It is specifically contemplated that such parallel methods, andin particular the above-detailed preferred parallel methods forevaluation of combinatorial libraries can be used in connection witheach and every other embodiment disclosed herein (e.g., evaluatinginteraction between a modifying agent and a receptor comprising naturalor artificial mammalian tissue, or other types of materials (as listedabove), evaluation protocols involving a reference chamber, etc.)—suchas test procedures (I) to (IV) as outlined above.

[0058] Individual test procedures having one or more of characteristics(I) to (IV) set out above are in themselves novel and inventive, andform part of the present invention. Thus, in second to fifth aspects,the present invention provides methods which are suitable for evaluatingthe interaction between a receptor and a modifying agent in the presenceof a liquid carrier and which respectively have one of characteristics(I) to (IV) set out above.

[0059] In a sixth aspect, the invention provides apparatus suitable forcarrying out the method of the first aspect of the invention wherein themodifying agent is one of the library and each of the test procedureshas characteristic (I) above, the apparatus comprising

[0060] (A) a test chamber for the solid phase comprising a receptor asdefined in characteristic (I) above;

[0061] (B) a reservoir for the liquid carrier;

[0062] (C) a pump for continuously extracting a stream of the liquidcarrier from the reservoir and passing the stream through the testchamber;

[0063] (D) an autodilution and sampling robot for sequentially injectinginto the stream of liquid carrier, before the stream passes through thechamber, a plurality of liquid test samples, each sample containing aninitial quantity of one of the library of modifying agents and eachsample being injected over a limited time so that only a distinct testsection of the liquid stream contains the sample; and

[0064] (E) a detector for examining the stream of liquid carrier leavingthe test chamber without removing anything from the stream and fordetermining for each sample the proportion of the initial quantity ofthe modifying agent remaining therein.

[0065] In a seventh aspect, the invention provides apparatus suitablefor carrying out the method of the first aspect of the invention whereinthe method has characteristic (II) above, the apparatus comprising atest chamber which contains the solid phase comprising the receptor andwhich has an efficiency of less than 80, preferably less than 50,especially less than 10, theoretical plates; and a reservoir, pump,autodilution and sampling robot and detector as in the apparatus of theseventh aspect of the invention.

[0066] In an eighth aspect, the invention provides apparatus which issuitable for carrying out the method of the first aspect of theinvention wherein the method has characteristic (IV) as defined above,and which comprises

[0067] (A) a test chamber containing the solid phase comprising thereceptor;

[0068] (B) a reference chamber which is free of any substance whichinteracts with the modifying agent;

[0069] (C) a reservoir for the liquid carrier;

[0070] (D) a main passageway from the reservoir;

[0071] (E) a first branch passageway which is connected to the mainpassageway has a junction and which leads from the main passageway tothe test chamber;

[0072] (F) a second branch passageway which leaves from the testchamber;

[0073] (G) a third branch passageway which is connected to the mainpassageway at the junction and which leads from the main passageway tothe reference chamber;

[0074] (H) a fourth branch passageway which leaves from the referencechamber;

[0075] (I) an exit passageway which combines the second and fourthbranch passageways;

[0076] (J) a pump for extracting a stream of the liquid carrier from thereservoir and passing it through the main passageway;

[0077] (K) an injector for injecting into the stream of liquid carrier,before the stream passes from the main passageway to the first and thirdbranch passageways, a liquid unit, containing an initial quantity of themodifying agent, the unit being injected over a limited time so thatonly a distinct section of the liquid stream contains the unit, and thesample being divided into a first sub-stream which contains a firstsample of liquid unit and which passes through the test chamber and asecond sub-stream which contains a second sample of the liquid unit andwhich passes through the reference chamber; and

[0078] (L) a detector for examining the stream of liquid carrier passingout of the exit passageway and for ascertaining the proportion of themodifying agent remaining therein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0079] The invention is illustrated in the accompanying drawings, whichare described briefly as follows.

[0080]FIG. 1 is a diagrammatic illustration of an apparatus forinjecting a plurality of liquid units into a stream of liquid carrier;

[0081]FIGS. 2, 4, 6, 9, 10 and 11 are diagrammatic illustrations ofapparatus for evaluating the interaction between a receptor and alibrary of modifying agents, by passing a stream containing successivesamples of the library through a chamber containing the receptor, andexamining the stream leaving the chamber with a detector, the apparatusof FIG. 11 also being suitable for evaluating the interaction between amodifying agent and a library of receptors; and

[0082]FIGS. 3, 5, 7 and 8 are plots of time against the amount ofmodifying agent remaining in the stream leaving the chamber, as recordedby the detectors in FIGS. 2, 4, 6, 9, 10 and 11.

DETAILED DESCRIPTION OF THE INVENTION

[0083] In the Summary of the Invention above, the Detailed Descriptionof the Invention, the Examples, and the Statements below, and theaccompanying drawings, reference is made to particular features of theinvention. It is to be understood that the disclosure of the inventionin this specification includes all appropriate combinations of suchparticular features. For example, where a particular feature isdisclosed in the context of a particular embodiment, a particularstatement, or a particular Figure, that feature can also be used, to theextent appropriate, in the context of other particular embodiments,Statements and Figures, and in the invention generally.

[0084] The detailed description below is directed to each aspect of theinvention, considered individually and in various combinations. Aspectsof the detailed description are chiefly directed to the first aspect ofthe invention, in which libraries of compositions are evaluated, and toapparatus for use in the first aspect of the invention. It is to beunderstood, however, that insofar as the detailed description isconcerned with test procedures having one or more of the characteristics(I) to (IV) above, it is also applicable to the second to sixth aspectsof the invention.

[0085] Receptors

[0086] The receptor can be any element, compound or composition which isa solid or which can be immobilized on a solid. Receptors that aresuitable, and indeed in some embodiments preferred, include thefollowing.

[0087] (1) Fabrics (i.e., a fabric material), including woven, knittedand nonwoven fabrics (including papers), made from natural or artificial(including regenerated natural) sources, such as continuous filament orstaple fiber yarns, for example polyamide, polyester, polyolefin,polyurethane, cellulosic, cotton, silk and wool yams. The particularform of the fabric material is not narrowly critical, and can includesheets of fabric materials, bulk fabric materials, stranded fabricmaterials (e.g. yarns), etc.

[0088] (2) Particulate materials, including particulate materials whichcomprise at least 50%, preferably at least 75%, e.g. 75-100%, by weightof particles having an aspect ratio of at least 2, preferably at least5, particularly at least 10, especially at least 50, e.g. at least 100,and optionally having at least one dimension greater than 100 micron,preferably greater than 500 micron.

[0089] (3) Continuous sheets of natural or synthetic (includingregenerated natural) organic polymers, including such sheets which arefree of open pores and preferably are substantially free of all pores.

[0090] (4) Foodstuffs, including coffee beans (green and roasted),ground coffee, meats, poultry, beans (e.g., soybeans), grains, cereals,rice, pastas, fruits and vegetables.

[0091] (5) Natural and artificial mammalian tissues, including forexample human or animal epidermis, epithelium, bone and hair. Moregenerally, the receptors of the invention can comprise biologicaltissue, including both natural and artificial biological tissue. A morespecific description of the mammalian tissue and/or more generally, thebiological tissue of the invention is set forth as follows.

[0092] (5a) The biological tissue (especially mammalian tissue) caninclude both natural and non-natural model biological tissue, as well asboth hard biological tissue and soft biological tissue. Detailsdiscussed hereinafter with regard to biological tissue, is particularlyintended to refer to mammalian tissues. In general, biological tissuecan be naturally occurring animal biological tissue or non-naturalbiological tissue (including both non-natural materials and naturalmaterials that are not natural biological tissues). Also, in general, itis preferred that the biological tissues used in the arrays and methodsof the present invention are soft biological tissues and/or hardbiological tissues. These tissues should preferably, in each case,fulfill the following requirements: (i) they should be chemically andphysically similar to human tissues (e.g., with respect to properties ofinterest, such as polymer adsorptivity), and (ii) and they should besuitable for high-throughput screening (e.g., with respect toavailability in sufficient quantities and reproducability to allow forcomparison between experiments of the screen).

[0093] (5b) A natural biological tissue can be an animal biologicaltissue, and in many cases, is preferably a human biological tissue, butcan also be an animal biological tissue such as bovine, porcine (pig),etc. Exemplary natural oral tissues include tissues from the tongue,teeth, heart, lungs, liver, kidney, spleen, brain vein, skin, blood,muscle, hair, etc. of animals, especially mammals such as humans andnon-human mammals, and especially of non-human mammals such as non-humanprimates, porcine (pig), bovine, rabbit, and mice, among others. Fororal care applications, for example, exemplary natural oral tissuesinclude human teeth (as an exemplary natural hard oral tissue), ortongue, such as porcine (pig) tongue (as an exemplary natural soft oraltissue), or gum, such as bovine or porcine gum (as an exemplary naturalsoft oral tissue) or cheek lining, such as bovine cheek lining (asanother exemplary soft oral tissue).

[0094] (5c) A model biological tissue can include both non-naturalmaterials, and natural materials that are not natural biologicaltissues. Model biological tissues preferably can have substantially thesame chemical properties as natural human biological tissue,particularly in an environment that is representative of the in-vivoconditions for the biological tissue of interest. In particular, themodel biological tissue is preferably effective for emulating naturalanimal biological tissue (e.g., natural human biological tissue ornatural bovine biological tissue or natural porcine biological tissue)for polymer adsorption to the biological tissue, typically in thepresence of a composition or atmosphere that is representative of, oremulates the natural composition or atmosphere in which the biologicaltissue is found. Especially, the model biological tissue is preferablyeffective for emulating natural oral tissue for polymers already knownin the art as having a certain degree of interaction, such asadsorptivity, with that biological tissue. For example, in oral careapplications, the model oral tissue is preferably effective foremulating natural oral tissue for polyoxyalkylene polymer adsorption tothe tissue in the presence of natural or artificial saliva. Preferably,as determined using the evaluation protocol of choice (e.g., asdescribed above), the degree of adsorptivity between the modelbiological tissue and the polymer of choice in the presence of theconditions that emulate the in vivo conditions for the tissue, can becomparable within at least about 50%, preferably at least about 30%,more preferably at least about 10%, and most preferably at least about5%, as compared to the degree of adsorptivity between polymer and thenatural animal biological tissue in the presence of such conditions.Exemplary model biological tissues include porous man-made polymericmaterials (as an example of non-natural model biological tissues),mineral-based materials (as an example of natural or non-natural modelhard tissues), epidermal (skin) or epithelium cells or other cells orsoft tissue (as an example of a natural material that is not a naturaloral tissue for a model soft oral tissue). More specific examples, fororal care applications, of model oral tissues include hydroxyapatite (asan example of a model hard oral tissue) and reconstructed epithelium (asan example of a model soft oral tissue).

[0095] (5d) For oral care applications, the oral tissue used accordingto the present invention is preferably selected from the group,consisting of a soft oral tissue, such as an animal tongue, especially apig tongue (emulating human tongue), a reconstructed epithelium(emulating human soft tissue such as cheek lining or gum), and a hardoral tissue, such as animal teeth, especially human teeth, andhydroxyapatite (emulating human teeth). Pig tongue provides reproducibleresults in high-throughput screening experiments and is a reliablesubstrate for high-throughput screening purposes. The surface area ofpig tongue is high enough to provide sufficient sensitivity todistinguish between adsorptivity of various polymers. Epitheliumreconstructed from human cells is commercially available from SkinEthics(France). Reconstructed epithelium also provides reproducible results inhigh-throughput screening experiments. The reconstructed epithelium maybe used in the form of small pieces provided on the bottom of the wellsof a microtiter plate, or in the form of strips of a larger piece ofepithelium. Human teeth are available from dental offices or otherdental supply sources, or from kids having ages ranging from about 4 toabout 10 years, preferably from about 5 to about 7 years. If the arrayof the present invention comprises hydroxyapatite (HAP), the form of theHAP is not narrowly critical, and can be varied depending on theapplication of interest. For example, the HAP can be in the form of asheet, disc, or powder. HAP powder or HAP in the form of discs iscommercially available (Clarkson Chromatography Products, Inc.; SouthWilliamsport, Pa.). HAP powder is preferred for some applications, andcan comprise particles having a size ranging from about 1 pm to about100 pm, preferably from about 5 pm to about 50 pm, and in general, canmore preferably consist essentially of particles having a size rangingin these same ranges. A preferred HAP powder comprises or consistsessentially of porous HAP particles having a particle size of from 10 to30 pm, preferably about 20 pm. HAP powder has a high surface area ofabout 7 to 8 m²/g (measured in accordance with the BET method andmercury porosimetry) and is characterized by the ability to averagedifferences among the individual HAP particles in a certain volume ofthe powder. Moreover, HAP powder does not show a significant fluorescentbackground. Therefore, quantitatively strong signals may be obtained.HAP powder is preferably used in the present invention. HAP discs have athin porous layer at the surface only and, therefore, are practicallyimpermeable. The surface area of HAP discs is about 0.1 m²/g.

[0096] (6) Compositions comprising a polysaccharide, protein (i.e. anamino acid polymer, including peptides, enzymes, biologically functionalproteins, etc.) or nucleic acid (i.e., a nucleic acid polymer, includingdeoxyribonucleic acid, ribonucleic acid, oligonucleotides andbiologically functional nucleic acid polymers). In particular, suchcompositions are preferred in combination with one or non-biologicalpolymers (e.g. provided as supports, linkers, brushes or otherwise. Forexample, the receptor can comprise a polysaccharide, protein (i.e.,amino acid polymer) or nucleic acid (i.e., nucleic acid polymer) as abiological probe, where the probes are presented using specificallydesigned non-biological polymer brushes (e.g., polymer-coated surfacesprepared for example through living free radical polymerizationtechniques). Such biological compositions presented on polymer brushesare described in co-owned PCT application WO 01/02452, and in thecorresponding co-owned U.S. applications, Ser. Nos. 09/347,606,09/347,607, 09/347,608 and 09/347,609, each of which is incorporatedherein by reference for all purposes.

[0097] (7) Catalyst, including catalyst comprising a metal, e.g. atransition metal or a Group IV metal, or a metal compound, or a protein,optionally supported by an in the support, e.g. a support composed of asilicate, a zeolite, alumina or another metal oxide.

[0098] (8) Elemental metals and metal alloys.

[0099] (9) Building materials including wood, concrete, natural stoneand artificial stone.

[0100] (10) Semiconductors.

[0101] (11) DNA chips, molecular recognition chips, and separationchips. DNA chips, as used herein, refer to an array of differentdeoxyribonucleic acid polymer molecules formed on, residing on, orsupported by or in a common substrate. Molecular recognition chips referto an array of different compounds or compositions that are selectivefor (i.e., selectively recognize) a particular chemical entity ofinterest, with such compounds or compositions being formed on, residingon or supported by or in a common substrate. An example of a molecularrecognition chip can include an arrays of monoclonal antibodies formedon a common substrate. Separation chips refer to array of differentcompounds or compositions that are functional for separating (e.g., bysize, by charge, by chemical composition, etc.) components of a mixture(e.g. components of a test sample), with such compounds or compositionsbeing formed on, residing on or supported by or in a common substrate.

[0102] Modifying Agents

[0103] The modifying agent can be any composition which can form atleast part of a liquid sample and which will interact with the receptor.The sample generally comprises a liquid in which a solid or fluidmodifying agent is dissolved, dispersed or emulsified. The liquid in thesample preferably does not interact with the receptor, and is preferablythe same as the liquid carrier. The concentration of the modifying agentin the sample is generally 0.001 to 10% by weight, preferably 0.05 to0.5% by weight.

[0104] Often the interaction between the receptor and the modifyingagent will be merely physical adsorption of the modifying agent on thesurface of the receptor. However, the interaction can alternatively oradditionally involve other types of interaction, including for exampleLewis acid/Lewis Base interaction, hydrogen bonding, occlusion, andclathration. In the first aspect of the invention, the objective isgenerally to identify the combinations of receptor, modifying agent andliquid carrier which result in the greatest retention of the modifyingagent in the test chamber. It is preferred, therefore, that in the leastone of the test procedures, at least 10%, particular least 20%, e.g.20-70%, or 30-50%, of the initial quantity of the modifying agent isretained in the test chamber. The variation in the results of the testprocedures may be for example such that there is a difference of least10, for example 10-70, often at least 25, for example 30-60, between (i)the percentage of the initial quantity of the modifying agent retainedin the test chamber in one of the test procedures and (ii) thepercentage of the initial quantity of the modifying agent retained inthe test chamber in another of the test procedures.

[0105] Organic polymers, including non-biological polymers and syntheticpolymers, are preferred modifying agents. The polymer can be, forexample, crystalline or non-crystalline, a thermoplastic or anelastomer, (including a thermoplastic elastomer), and a homopolymer orcopolymer, for example a polyamide, a polyester, a polyurethane, apolyether, a polyurea, or a polymer comprising units derived from atleast one ethylenically unsaturated monomer, e.g. an olefin, a vinylmonomer, or acrylic or methacrylic acid or an ester or amide thereof.Suitable polymers include polymers containing polar groups, e.g. ahydroxyl group, a primary, secondary or tertiary amino group(substituted or unsubstituted), or a carboxyl, sulfonyl or other acidicgroup or a salt or ester thereof.

[0106] The modifying agents of the invention can also includetherapeutic agents and/or diagnostic agents, themselves, and/or incombination with non-biological polymers (i.e., non-biological organicpolymers). As used herein, therapeutic agents includes prophylacticagents. Hence, the modifying agents can be chemical or biologicalentities that provide a diagnostic benefit for identifying ordetermining a particular state or condition such as a particular malady,medical concern or health concern, that provide a therapeutic benefitfor a particular malady or medical concern or health concern, and/orthat provide a prophylactic benefit, to avoid a particular malady ormedical concern or health concern. When such therapeutic agents ordiagnostic agents are used in combination with non-biological polymers,either the agents or the non-biological polymers or both can be membersof a combinatorial library. In some embodiments, differentnon-biological polymers are preferably members of a combinatoriallibrary being evaluated for interaction with a receptor, for example,such as a mammalian tissue, or other biological tissue.

[0107] When the modifying agent contains two or more compounds,including polymer molecules of different molecular weights, there may besome separation of those compounds as they pass through the testchamber. Such separation is not generally desired or useful for thepurposes of the present invention and preferably does not take place. Ifsuch separation does take place, and the detector measures both theseparated compounds, a plot of time against the concentration of themodifying agent in the stream leaving the test chamber will evidencethat separation. In some cases, the plot will show more than one peak,each peak corresponding to one of the separated components of themodifying agent. Preferably the plot has a principal peak which, whenthe plot is subjected to valley-to-valley integration, amounts to atleast 70%, preferably at least 80%, of the area under the curve. It isparticularly preferred that the plot has only a single peak, with theslope of the plot being positive at all points on one side of the peakand negative at all points on the other side of the peak.

[0108] Liquid Samples

[0109] The liquid samples are preferably small in size, so that they canbe injected in a very short time, e.g. a fraction of the second, intothe stream of liquid carrier. For example, the volume of the liquidsample may be, for example from 1 to 500 microliters, preferably from 5to 50 microliters. The samples are generally injected at a time intervalof not more than 10 minutes, preferably one every 0.15 to 3 minute.

[0110] Liquid Carriers

[0111] The liquid carrier can be any liquid which can be passed over thesolid phase in the test chamber and which permits satisfactoryascertainment of a property of the modifying agent. Generally, theliquid carrier can include water, aqueous solvents, non-aqueous polarsolvents and/or non-polar solvents. Preferably, there will besubstantially no interaction between the liquid carrier and the solidphase. The liquid carrier can be aqueous, organic or a mixture ofmiscible aqueous and organic liquids. Preferred liquid carriers areaqueous solutions of inorganic salts optionally containing surfaceactive agents, e.g. laundry additives, particularly solutions of thekind found in clothes washing machines and dishwashers. Other liquidcarriers are organic solvents of the kind used in the dry cleaning ofclothes, optionally containing surface active agents. When the libraryis a library of liquid carriers, the liquid carriers can for example beaqueous solutions which differ from each other in pH or temperature orboth.

[0112] Libraries

[0113] In each of the test procedures in the methods of the first aspectof the invention, one of the receptor, modifying agent and liquidcarrier is a member of a library. In preferred embodiments, the librarymembers are either receptors or modifying agents, such that members areevaluated for interaction between a receptor member of the combinatoriallibrary and a modifying agent, or alternatively for interaction betweena modifying agent member of a combinatorial library and a receptor, ineach case in the presence of a liquid carrier. Regardless of thecharacterization of the library members, the library generally containsat least four members and may contain many more, for example up to 96members. Sometimes all the members of the library are tested, but thisis not necessary. Generally at least four test procedures are carriedout, using a different member of the library in each test procedure. Ifnot all the members of a library are tested, the tested members willgenerally be taken from different sections of the library. If not allmembers of a library are tested, the results of the steps (c) can beused to select one or more members of the library for further testing.The selected member(s) may be member(s) which were tested and/ormember(s) which were not tested. Different library members may bescreened simultaneously using the same test procedures (ie., screenedunder a common set of conditions using common protocols), and/or thedifferent library members may be screened sequentially.

[0114] The invention is particularly useful when the library is alibrary of modifying agents, because it is then possible to use aconventional autodilution and sampling robot to inject the differenttest samples into the stream of liquid carrier (e.g., in sequentialfashion). Furthermore, when, as is preferred, the surface area of thesolid phase is relatively large by comparison with the amount of themodifying agent, the members of the library can be tested in series,with the stream of liquid carrier, containing the different samples insequence, being passed through the same test chamber. This isparticularly advantageous where each sample does not saturate the solidphase receptor. In this way, a rapid rate of testing can be maintained,and moreover, can be multiplied particularly if at least two, e.g. fouror more, substantially identical test chambers are used in parallel. Bycontrast, when the library is a library of receptors, a plurality oftest chambers, each containing a different receptor, can be individuallyprepared, and they are preferably tested in parallel. Alternatively, theplurality of different individual receptors can be presented for testingin a single flow-channel system by alternately and successivelyreplacing one test chamber (comprising a solid phase having a receptorcomprising one member of the library) with the next test chamber(comprising a solid phase having another receptor comprising anothermember of the library). When the library is a library of liquidcarriers, they too can be tested in parallel, or with proper hardwareconfiguration, in series.

[0115] When the library is a library of modifying agents, anyappropriate diversity element can form the basis of the library. Forexample, the library of modifying agents can comprise four or moredifferent therapeutic agents or can comprise four or more differentdiagnostic agents, especially for screening with biological tissue suchas mammalian tissue. Other diversity elements are well known in the art,especially for small organic molecules, enantiomeric molecules and formolecules having biological and/or pharmaceutical activity. The libraryof modifying agents can, in any case, further comprise non-biologicalpolymers. The same common non-biological polymers can be used inconnection with the library (e.g., when a different chemical entity suchas a therapeutic or diagnostic agent is employed as the diversityelement of the library). Alternatively, and in one particularlypreferred embodiment, the non-biological polymers can be the diversityelement of the library, and can preferably (but not necessarily) beapplied to a same common agent such as a same common diagnostic agent ortherapeutic agent. The library of modifying agents can also have morethan one diversity elements, including for example at least four membersthat vary with respect to two or more features (e.g. differentnon-biological polymer and different therapeutic and/or diagnosticagent).

[0116] The combinatorial library can be also be a library of receptors.The library of receptors can include different receptor materials.Hence, when the receptors comprise mammalian tissue, the library cancomprise different natural or artificial mammalian tissue. The variationin the receptors as compared between members of such a library caninclude the specific nature of the tissue, the source of the tissue, thepretreatment history of the tissue, etc. The different receptormaterials can, in a preferred embodiment, include differentnon-biological polymers to create diversity between members of thelibrary. For example, a same common receptor material (e.g., mammaliantissue, fabric materials, etc.) can be pretreated (e.g. by coating,immersion, etc.) with a different non-biological organic polymer. Inthis way, various treatment agents and protocols for a given receptor(e.g. mammalian tissue, fabric materials) can be investigated todetermine a preferred non-biological treatment agent and protocol. Aspecific example of such application relates to skin care and/or woundcare, in which the receptor can comprise skin cells (e.g. epidermalcells, epithelium cells) that have been pretreated with variousdifferent non-biological polymers to form a library of differentreceptor materials. The different receptor materials can then bescreened by exposure to a same common modifying agent to determine theinteraction between the modifying agent and the different receptormaterials.

[0117] Detectors

[0118] The term “detector” is used herein to denote any instrument whichcan be used to ascertain a property of the modifying agent in the streamof liquid carrier (including, as noted above, a property of part of themodifying agent and a property of a substance which is produced by theinteraction of the modifying agent and the receptor). Hence, thedetector can be a flow detector as known in the chromatographic arts.Preferably the detector operates without removing anything from thestream (i.e. is non-destructive). Such detectors measure, for example,(i) the adsorption by the liquid stream of radiation whose wavelength isabsorbed to by the modifier but not by the liquid carrier, (ii) thefluorescence of the stream, or (iii) the refractory index of the stream.The detector often makes a series of measurements at spaced intervals oftime, and (via transducers and amplifiers) produces a concentrationprofile from which, for example, the total quantity of the modifyingagent in the stream and the peak value of the concentration of themodifying agent can be determined. The detector may measure the presenceor absence of a particular ingredient, and may produce results in theform of a graph having a maximum or a minimum, each of which is referredto herein as a “peak”. Such detectors are well-known to those skilled inthe art. Additional useful information may be available from the shapeof the concentration profile. For example the more symmetrical the peak(i.e. the smaller the size of the tail representing material which isextracted from the solid phase by the subsequent stream of liquidcarrier), the less reversible the interaction between the modifyingagent and the receptor. The center of gravity of the concentrationprofile (i.e. the time at which half of the total detected amount of themodifying agent has passed through the detector) shows the averageretention time of the modifying agent in the test chamber. FIGS. 3, 5, 7and 8 are typical plots of time against a measured value which isdirectly proportional to the amount of the modifying agent in the streamleaving the test or reference chamber.

[0119] Test Chambers

[0120] The test chamber can be any structure which will contain thesolid phase so that the stream of liquid carrier can be passed over it.Hence, the test chamber typically has at least one inlet and at leastone outlet. The volume of test chamber will often be from 0.01 to 50 mL,preferably 0.2 to 5 mL. The test chamber will often be cylindrical, witha diameter of 0.1 to 30 mm, preferably 1 to 8 mm, and a length of 1 to150 mm, preferably 3 to 30 mm. However, chambers of other shapes can beused, typically with the same cross-sectional areas and lengths. Thesolid phase can be retained within the test chamber in any way. Oftenthe solid phase is packed within the chamber so that the stream ofliquid carrier flows through the chamber at a linear velocity of 0.01 to10, preferably 0.5 to 2, cm/min and/or a flow rate of 0.01 to 50,preferably 0.5 to 5, mL/min. The efficiency, of the test chamber, withthe solid phase therein, is generally less than 80 theoretical plates,preferably less than 50 theoretical plates, particularly less than 10theoretical plates, and in many cases is 2-5, for example 3-4,theoretical plates.

[0121] Reference Chambers

[0122] In some embodiments of the invention, the need to determineabsolute amounts of the modifying agent is eliminated by passing areference sample through a reference chamber. Hence, the referencechamber has at least one inlet and at least one outlet. The referencechamber is free of any substance which interacts with the modifyingagent, and in some cases is simply empty. That is, the reference chamberhas an essential absence of interferring solid phase media—especiallysolid phase media that would interfere substantially with the evaluationof the reference section. Hence, the reference chamber can comprisematerials that are interactively inert with respect to the test sample,and particularly, with respect to the modifying agent in the testsample. Examination of the stream leaving the reference chamber providesa reference standard from which the proportion of the modifying agentretained in the test chamber can be ascertained. When the streamsleaving the test and reference chambers are examined by differentdetectors, their void volumes are preferably substantially the same (forexample, from 0.8 to 1.2 times the arithmetic average of their voidvolumes). When the liquid stream is split, and the two resultingsub-streams are passed through the test and reference chambers,recombined and examined by the same detector, the void volumes of theloops containing the test and reference chambers can be sufficientlydifferent that the detector can distinguish between the sections whichhave passed through the different chambers. The sections need not beentirely distinct, provided that the amount of modifying agent in eachcan be ascertained with sufficient accuracy for the purposes of theinvention. For example, the smaller of the void volumes can be 0.5 to0.8 times the larger of void volumes. The void volume of a chamber isits total volume less the volume occupied by any solid material therein.

[0123] Test Procedures

[0124] Generally the temperature, pressure, flow rates, sample sizes,and other test conditions are the same in each of the test proceduresand the receptor, modifying agent and liquid carrier are the same ineach of the test procedures, except that in each test procedure adifferent member of the library is used. Often all the test proceduresare substantially identical except for the use of the different memberof the library. However, this is not necessary. For example, thedetector can be programmed simply to report that the test was negativeif the peak height of the concentration profile is over a particularvalue; or there can be a feedback loop to change the rate of flow of theliquid carrier in response to the results in earlier tests. In addition,the invention includes the possibility that at least some of the testprocedures (i) differ only in the test conditions, or (ii) differ in thetest conditions and otherwise differ only in that each test procedureuses a different member of the library, or (iii) use the same conditionsin the test procedures and otherwise differ in that more than one of thereceptor, modifying agent and liquid carrier are changed (for example,when more than one of the receptor, modifying agent and liquid carrierare selected from libraries, different members are selected from two orthree of the libraries).

[0125] The flow rate of liquid carrier through the test chamber isgenerally 1-10, preferably 2-6, especially 3-5, mL/min.

[0126] The conditions in the test chamber can be such that the change inthe pressure within the test chamber changes, or does not change, theflow rate of liquid carrier. A graph of the flow rate of the liquidcarrier against the pressure in the test chamber generally reaches aplateau at a pressure of less than 5000, preferably less than 1000,particular less than 500, especially less than 100, psi.

DESCRIPTION OF THE DRAWINGS

[0127]FIG. 1 is a diagrammatic illustration of an apparatus forinjecting a plurality of liquid units into a stream of a liquid carrier,each unit comprising a modifying agent which is one of a library. InFIG. 1, a liquid carrier 10 is stored in reservoir 11. Pump 12 conveysliquid carrier from the reservoir 11 to an injection port 13. Microtiterplate 14 and injection needle 15 are part of a conventional autodilutionand sampling robot. Members of the library are retained separately onthe microtiter plate 14 and are sequentially removed by the injectionneedle 15 and diluted with carrier liquid from the reservoir 11 to formunits containing one of the members of the library. The units are thentransported to the injection port 13, where they are injectedsequentially into the stream of liquid carrier. After passing throughfilter 16, the stream of liquid carrier, carrying the units in distinctsections, is conveyed down line 17.

[0128]FIG. 2 is a diagrammatic illustration of a first apparatus forevaluating the interaction between a solid phase comprising a receptorand a library of modifying agent. A stream of liquid carrier is fed tothe apparatus through line 17 (for example from apparatus as illustratedin FIG. 1). The stream contains liquid units in distinct sections, andeach unit comprises a modifying agent which is one of the library ofsecond materials. The stream passes through a test chamber 22 containinga solid phase comprising the receptor, and then through a detector 24,before being discarded. The test chamber has an inlet for receiving theliquid carrier, and the liquid test sample in the distinct test sectionthereof, in fluid communication with a an upstream source of the carrierliquid. The test chamber also has an outlet for discharging the carrierliquid after it has passed through the test chamber, the outlet being influid communication with a detector 24. The detector 24 ascertains theamount of the modifying agent remaining in the stream.

[0129]FIG. 3 is a typical plot of time against the response of thedetector 24 in FIG. 2, for a section of the stream containing amodifying agent which is partially adsorbed by the receptor. In FIG. 3(and in the other Figures showing the response of the detector), thereis a base level which represents the response of the detector to theliquid carrier alone (or to the liquid carrier containing a very smallamount of modifying agent which results from the extraction of modifyingagent which was deposited on the solid phase in earlier testprocedures). The amount of modifying agent in the stream can becalculated from the area under the curve, above the base level. Theheight of the peak and the shape of the curve can also provide otherinformation about the interaction between the modifying agent and thefirst solid material. If the amount of the modifying agent originallypresent in the unit is known, then the amount-retained in the testchamber can be calculated from a plot of the type shown in FIG. 3.

[0130]FIG. 4 is a diagrammatic illustration of a second apparatus forevaluating the interaction between a receptor and a library of modifyingagents. This apparatus makes it possible to determine the percentage ofthe modifying agent retained by the receptor and is not dependent on theamount of modifying agent originally present in the sample. A stream ofliquid carrier is fed to the apparatus through a main passageway, suchas line 17 (for example from apparatus as illustrated in FIG. 1). Thestream contains liquid units in distinct sections and each unitcomprises a modifying agent which is one of the library. The mainpassageway provides fluid communication between a liquid carrier source(e.g., such as reservoir 11 as shown in FIG. 1) and a flow splitter,such that the liquid unit is divided by the valve 41 into first andsecond substreams. The splitter is illustrated in FIG. 4 as switchingvalve 41, which itself is in fluid communication with two or more branchpassageways. As illustrated, switching valve 41 is in fluidcommunication with a first loop defined by a first branch passagewayproviding fluid communication to an inlet of the test chamber 42, thetest chamber 42 itself, and second branch passageway providing fluidcommunication from an outlet of the test chamber 42 to a common exitpassageway. Switching valve 41 is also in fluid communication with asecond loop defined by a third branch passageway providing fluidcommunication to an inlet of a reference chamber 43, the referencechamber 43 itself, and a fourth branch passageway providing fluidcommunication from an outlet of the reference chamber 43 to the commonexit passageway. As each unit-carrying section of the liquid streamreaches the switching valve 41, the valve passes a first part of thesection containing half of the modifying agent through the first loopcontaining test chamber 42 and a second part of the section containingthe other half of the modifying agent through the second loop containingreference chamber 43. The order in which this is done is not important.(That is, for example, the first part of each unit-carrying sectioncould be directed to the reference chamber loop, and the second part ofeach unit-carrying section could be directed to the test chamber loop.The test chamber 42 contains a solid phase comprising the receptor. Thereference chamber 43 is empty or contains a material which does notinteract with the modifying agent (that is, does not not interact to adegree having a substantial effect on the comparison). The void volumesof the first and second loops are preferably substantially the same, butcan also be different in some embodiments. For example, the void volumesof the loops containing the chambers 42 and 43 can be sufficientlydifferent that, when the first and second sub-streams are recombined,the detector 44 can ascertain, for each section, the amounts of themodifying agent remaining in the parts of the recombined stream whichcorrespond to the first and second sub-streams. Preferably, the firstand second parts of the stream return sequentially from the chambers 42and 43 respectively to the valve 41 and are recombined in a common exitpassageway to form a common exit carrier stream, and are then passedsequentially through a detector 44, before being discarded. Thedetector, 44 is in fluid communication with the common exit passagewayand can be used to ascertain the amounts of the modifying agentremaining in the first and second parts of the stream respectively.

[0131]FIG. 5 is a typical plot of time against the concentration of themodifying agent, as measured by the detector 44 in FIG. 4, for a sectionof the stream containing a modifying agent which is partially adsorbedby the receptor. In this plot, the first curve, containing the sharperand higher peak, is for the modifying agent which passed through thereference chamber, and the second curve, containing the broader andlower peak, is for the modifying agent which passed through the testchamber. If the area under the first curve is A5 a, and the area underthe second curve is A5 b, the percentage of the modifying agent retainedin the test chamber is (A5 a−A5 b)/A5 a. The height of the peak and theshape of the second curve can also provide other information about theinteraction between the modifying agent and the receptor.

[0132]FIG. 6 is a diagrammatic illustration of a third apparatus forevaluating the interaction between a receptor and a library of modifyingagents. Like the apparatus shown in FIG. 4, this apparatus makes itpossible to determine the percentage of the modifying agent retained inthe test chamber and is not dependent on the amount of modifying agentoriginally present in the sample. Furthermore, unlike the apparatus ofFIG. 4, the flow splitter is a stream-splitting junction 61 rather thana switching valve (41, FIG. 4). The junction 61 will consistently directone half of the modifying agent through the test chamber and the otherhalf through the reference chamber. A stream of liquid carrier is fed tothe apparatus of FIG. 6 through a main passageway, such as for exampleline 17 (for example from apparatus as illustrated in FIG. 1). Theliquid carrier carries liquid units in distinct sections, and each unitcomprises a modifying agent which can be one of the library members. Themain passageway provides fluid communication between a liquid carriersource (e.g., such as reservoir 11 as shown in FIG. 1) and a flowsplitter, such that the liquid unit is divided by the stream-splittingjunction 61 into first and second substreams. Junction 61 is itself isin fluid communication with two or more branch passageways.Specifically, as illustrated, when the liquid stream reaches junction61, the stream splits into a first sub-stream and a second sub-stream.Junction 61 is in fluid communication with a first loop defined by afirst branch passageway providing fluid communication to an inlet of thetest chamber 62, the test chamber 62 itself, and second branchpassageway providing fluid communication from an outlet of the testchamber 62 to a common exit passageway. Junction 61 is also in fluidcommunication with a second loop defined by a third branch passagewayproviding fluid communication to an inlet of a reference chamber 63, thereference chamber 63 itself, and a fourth branch passageway providingfluid communication from an outlet of the reference chamber 63 to thecommon exit passageway. In operation, the first sub-stream passesthrough the first loop containing test chamber 62 and the secondsub-stream passes through the second loop containing reference chamber63. The test chamber 62 contains a solid phase comprising the receptor.The reference chamber 63 is empty or contains a material which does notinteract with the modifying agent. The first and second sub-streams arerecombined after leaving the chambers 62 and 63 respectively, into acommon exit passageway in fluid communication with a detector 64. Therecombined stream is passed through the detector 64, before beingdiscarded. The void volumes of the loops containing the chambers 62 and63 can be the same, but are preferably sufficiently different that, whenthe first and second sub-streams are recombined, the detector 64 canascertain, for each section, the amounts of the modifying agentremaining in the parts of the recombined stream which correspond to thefirst and second sub-streams.

[0133]FIG. 7 is a typical plot of time against the concentration of themodifying agent, as measured by the detector 64 in FIG. 6, for a sectionof the stream containing a liquid sample in which the modifying agent ispartially adsorbed by the receptor. In this plot, the first curve,containing the sharper and higher peak, is for the modifying agentremaining in the part of the stream which passed through the emptychamber, and the second curve, containing the broader and lower peak, isfor the modifying agent remaining in the part of the stream which passedthrough the chamber containing the first solid material. In order toascertain from FIG. 7 the percentage of the modifying agent retained inthe test chamber, it is necessary to know the flow splitting ratiobetween the test chamber and the reference chamber. The flow splittingratio can be ascertained by replacing the library material by anadditive which does not interact with the solid phase in the testchamber.

[0134]FIG. 8 is a typical plot of the concentration of such an additive,as measured by the detector 64. In this plot, the first curve,containing the sharper and higher peak, is for the additive which passedthrough the empty chamber, and the second curve, containing the broaderand lower peak, is for the additive which passed through the chambercontaining the first solid material. The flow splitting ratio (FSR) isthe ratio of the area under the first curve to the area under the secondcurve. If the area under the first curve in FIG. 7 is A7 a, the areaunder the second curve in FIG. 7 is A7 b, the area under the first curvein FIG. 8 is A8 a, and the area under the second curve in FIG. 8 is A8b, the percentage of the modifying agent retained in the test chamber is100 −[100×A7 a/A7 b×A8 a/A8 b]. The shape of the second curve can alsoprovide information about the rate of interaction between the modifyingagent and the first solid material.

[0135]FIG. 9 is a diagrammatic illustration of a fourth apparatus forevaluating the interaction between a receptor and a library of modifyingagents. In FIG. 9, a first stream of carrier liquid is fed through line17 a (for example from apparatus as illustrated in FIG. 1). The streamcontains liquid samples in distinct sections and each sample comprises amodifying agent which is one of the library. The stream passes through atest chamber 92 which contains a solid phase comprising the receptor,and then through a detector 94 a, before being discarded. A secondstream, identical to the first stream, is fed through line 17 b (forexample from apparatus as illustrated in FIG. 1), through a referencechamber 93 which is empty or contains a material which does not interactwith the modifying agent, and then through a detector 94 b, before beingdiscarded.

[0136]FIG. 10 is a diagrammatic illustration of a fifth apparatus forevaluating the interaction between a receptor and a library of modifyingagents. In FIG. 10, a stream of carrier liquid is fed through line 17(for example from apparatus as illustrated in FIG. 1). The streamcontains liquid samples in distinct sections and each sample. comprisesa modifying agent which is one of the library. The stream passesconsecutively through a reference chamber 103 which is empty or containsa material which does not interact with the modifying agent, a firstdetector 104 b, a test chamber 102 which contains a solid phasecomprising the receptor, and second detector 104 a, before beingdiscarded.

[0137] The proportion of modifying agent retained in the test chamber inFIGS. 9 and 10 can be determined in the way described above for FIGS. 4and 5.

[0138]FIG. 11 is a diagrammatic illustration of a sixth apparatus forevaluating the interaction between a receptor and a library of modifyingagents. In a stream carrier liquid is fed through line 17 (for examplefrom apparatus as illustrated in FIG. 1). The stream contains liquidsamples in distinct sections and each sample comprises a modifying agentwhich is one of the library. The sample-carrying stream is fed to avalve 111 which sequentially directs successive sub-streams, eachsub-stream containing a single sample, to a loop containing a referencechamber 113 and to one of a plurality of loops each containing a testchamber 112 a,b,c . . . Four test chambers are shown in FIG. 11, but anyappropriate number, for example from 2 to 64, could be used. Each of thetest chambers contains a solid phase comprising the receptor. Thereference chamber is empty or contains a material which does notinteract with the modifying agent. The liquid sub-streams, after passingthrough the reference or test chamber, are recombined into a singlecombined stream containing substantially separate evaluation sectionscorresponding to the samples. The combined stream is passed through adetector 114, which detects the amount of modifying agent in each of theevaluation sections in turn.

[0139] The apparatus of the type shown in FIG. 11 can also be used toevaluate the interaction between a modifying agent and a library ofreceptors. In this case, the liquid samples in the stream are identical,and the solid phase in each of the test chambers comprises one of thelibrary of receptors. In apparatus of the type shown in FIG. 11, thesingle detector 114 could be replaced by a plurality of detectors, eachexamining a single sub-stream or a suitable proportion of thesub-streams.

EXAMPLES

[0140] The invention as illustrated in the following Examples.

Example 1

[0141] Apparatus of the type shown in FIGS. 1 and 4 was used to evaluatethe interaction between (i) a copolymer of N-(3-(dimethylamino) propyl)methacrylamide, styrene and acrylic acid, in a molar ratio of98.3:0.1:0.12, and (ii) a cotton fabric. The cotton fabric was a plainwhite untreated cotton sheet, about 50 mm wide, rolled tightly andinserted into the column. The pump was a high performance liquidchromatography (HPLC) pump sold by Waters under the tradename Model 515.The injection port was a two-position injection valve sold by Valcounder the tradename Model EHMA. The valve was equipped with two 50microliter injection loops. The multiposition switching valve was avalve sold by Valco under the tradename Model EMTMA-CE.

[0142] The liquid carrier was a 1% by weight solution of ammoniumacetate in deionized distilled water to which had been added sufficientammonium hydroxide to bring the pH to 10.5 and 1% by weight of a stockdetergent solution. The stock detergent solution was composed of ionizeddistilled water to which had been added 0.6 g/L of a proprietary linearalkane sulfonate, 0.4 g/L. of a proprietary non-ionic surfactant, 1.25g/L. of sodium carbonate, 1.1 g/L. of pentasodium triphosphate, 1.0 g/L.sodium chloride and 0.0882 g/L. of calcium chloride dihydrate. The flowrate of the liquid carrier was about 4 mL/min.

[0143] The liquid sample contained 2 mg/mL of the copolymer dissolved inthe liquid carrier. The time between the injections was 2 minutes.

[0144] The test chamber was a stainless steel column having a height of50 mm and an internal diameter of 7.5 mm, with the cotton fabric tightlyrolled to completely fill the column. The reference chamber was aproprietary on-line pre-column HPLC metal filter sold by ValcoInstruments. The passageways connected to the first and second chamberswere sized to insure that the void volumes of the first and second loopswere substantially the same.

[0145] The detector was an evaporative light scattering detector sold byPolymer Laboratories under the tradename Model ELSD-1000. The resultsobtained by the detector are shown in FIG. 5.

Example 2

[0146] Apparatus of the type shown in FIGS. 1 and 6 was used to evaluatethe interaction between (i) the cotton fabric used in Example 1 and (ii)(a) the copolymer used in Example 1, and (b) a library of 96 differentpolymers each composed of units derived from three monomers. Details ofthe polymers in the library are shown in Table 1 below, which gives theproportions by weight of the units derived from each of the threemonomers, the first figure being for units derived from4-acetoyloxymethyl) styrene, the second figure being for units derivedfrom 2-hydroxyethyl methacrylate, and the third figure being for unitsderived from 2-(dimethylamino) ethyl methacrylate.

[0147] The autodilution and sampling robot, the pump, the injection portand the detector were as described in Example 1. The test chamber andthe reference chamber were as described in Example 1, but thepassageways to and from them were sized so as to insure that, in thecombined stream entering the detector, the samples from the respectivechambers were substantially separated so that they could be ascertainedseparately by the detector.

[0148] The liquid carrier, and its flow rate, were as in Example 1.

[0149] The liquid sample contained about 2 mg/mL of the polymerdissolved in a liquid carrier, and each sample was about 50 microliters.The time between the injections was 3 minutes.

[0150] The results obtained by the detector are shown in FIG. 5. TABLE 11 2 3 4 5 6 7 8 9 10 11 12 1 30 30 30 30 30 30 30 30 30 30 30 30 69 6458 53 47 41 36 30 25 19 13 41 1 6 12 18 23 29 34 40 46 51 57 29 2 25 2525 25 25 25 25 25 25 25 25 25 74 68 62 56 50 44 38 32 26 20 14 44 1 7 1319 25 31 37 43 49 55 61 31 3 20 20 20 20 20 20 20 20 20 20 20 20 79 7366 60 54 47 41 34 28 22 15 47 1 7 14 20 26 33 39 46 52 58 65 33 4 15 1515 15 15 15 15 15 15 15 15 15 84 77 71 64 57 50 43 37 30 23 16 50 1 8 1421 28 35 42 48 55 62 69 35 5 10 10 10 10 10 10 10 10 10 10 10 10 89 8275 68 60 53 46 39 32 24 17 53 1 8 15 23 30 37 44 51 59 66 73 37 6 8 8 88 8 8 8 8 8 8 8 8 92 84 77 69 62 55 47 40 32 25 18 55 1 8 16 23 31 38 4553 60 68 75 38 7 5 5 5 5 5 5 5 5 5 5 5 5 94 86 79 71 64 56 48 41 33 2618 56 1 9 16 24 31 39 47 54 62 69 77 39 8 3 3 3 3 3 3 3 3 3 3 3 3 97 8981 73 65 58 50 42 34 26 19 58 1 9 17 24 32 40 48 56 63 71 79 40

[0151] In order to determine the flow splitting ratio of the apparatus,a sample of poly(N-vinylpyrrolidone), a polymer which does not interactwith the cotton fabric, is passed through the apparatus. FIG. 8 showsthe results recorded by the detector. The area A3 under the narrow,higher peak, from the stainless-steel filter, was about 43,000. The areaA4 under the broad, lower peak, from the first chamber containing thecotton fabric, was about 62,800. Thus the flow splitting ratio was0.685.

[0152] A sample of the copolymer used in Example 1 was then passedthrough the apparatus. FIG. 7 shows the results recorded by thedetector. The area A1 under the narrow, higher peak, from thestainless-steel filter, was about 65,900. The area A2 under the broader,lower peak, from the first chamber containing the cotton fabric, wasabout 70,500. The percentage of the copolymer remaining in the liquidstream which had passed through the first chamber was, therefore, about73%, i.e. (70500/65900)×0.685, and the percentage that had been retainedby the cotton fabric was about 27%.

[0153] Samples of each of the 96 members of the library were then passedthrough the apparatus and the percentage of each,retained by the cottonfabric was calculated. The results are shown in Table 2 below. TABLE 2 12 3 4 5 6 7 8 9 10 11 12 1 0 10 18 3 38 40 41 46 59 45 32 0 2 0 0 23 4847 46 54 52 58 45 50 0 3 0 16 13 45 39 41 58 48 56 44 28 0 4 0 13 9 2031 36 27 15 32 36 16 4 5 0 1 5 0 2 16 6 8 19 21 16 19 6 0 0 0 0 0 0 4 57 9 24 0 7 0 0 0 0 0 0 3 0 15 17 22 46 8 0 0 8 0 0 0 4 6 5 18 23 0

[0154] In light of the detailed description of the invention and theexamples presented above, it can be appreciated that the several objectsof the invention are achieved.

[0155] The explanations and illustrations presented herein are intendedto acquaint others skilled in the art with the invention, itsprinciples, and its practical application. Those skilled in the art mayadapt and apply the invention in its numerous forms, as may be bestsuited to the requirements of a particular use. Accordingly, thespecific embodiments of the present invention as set forth are notintended as being exhaustive or limiting of the invention.

We claim:
 1. A method for evaluating the interaction between a receptorcomprising a selected material and a modifying agent in the presence ofa liquid carrier, the method comprising a test procedure comprising (a)injecting a liquid test sample into a stream of the liquid carrier, thetest sample comprising the modifying agent, the injection being carriedout over a limited time so that a distinct test section of the streamcontains the test sample, (b) passing the stream of liquid carriercontaining the test sample over a solid phase in a test chamber, thesolid phase comprising the receptor, the receptor comprising a materialselected from the group consisting of a fabric, a substantiallypore-free sheet of an organic polymer, a foodstuff, wood, concrete,natural or artificial stone, and a semiconductor, and (c) examining thestream of liquid carrier leaving the test chamber to ascertain avariable which reflects the interaction of the modifying agent and thereceptor in the presence of the liquid carrier.
 2. A method forevaluating the interaction between a receptor comprising a selectedmaterial and a modifying agent in the presence of a liquid carrier, themethod comprising providing the receptor comprising a material selectedfrom the group consisting of a fabric, a substantially pore-free sheetof an organic polymer, a foodstuff, wood, concrete, natural orartificial stone, and a semiconductor, and providing the modifyingagent, one of the receptor and modifying agent being provided as amember of a combinatorial library having at least four members,conducting at least four test procedures with the receptor, modifyingagent and liquid carrier being the same in each of the test proceduresexcept that in each test procedure a different member of thecombinatorial library is used, each of the test procedures comprising(a) injecting a liquid test sample comprising the modifying agent into astream of the liquid carrier, the injection being carried out over alimited time so that a distinct test section of the stream contains thetest sample, (b) passing the stream of liquid carrier containing thetest sample over a solid phase in a test chamber, the solid phasecomprising the receptor, and (c) examining the stream of liquid carrierleaving the test chamber to ascertain a variable which reflects theinteraction of the modifying agent and the receptor in the presence ofthe liquid carrier.
 3. A method for evaluating the interaction between areceptor comprising a selected material and a modifying agent comprisinga non-biological polymer in the presence of a liquid carrier, the methodcomprising providing the receptor comprising a material selected fromthe group consisting of a fabric, a substantially pore-free sheet of anorganic polymer, a foodstuff, wood, concrete, natural or artificialstone, a semiconductor, a polysaccharide, a protein or a nucleic acid, acatalyst, an elemental metal, a deoxyribonucleic acid chip, a molecularrecognition chip and a separation chip, providing the modifying agentcomprising a non-biological polymer, the modifying agent being providedas a member of a combinatorial library having at least four members,each of the at least four members of the library comprising a differentnon-biological polymer, conducting at least four test procedures withthe receptor and liquid carrier being the same in each of the testprocedures, and with a different member of the combinatorial librarybeing used in each of the at least four test procedures, each of thetest procedures comprising (a) injecting a liquid test sample comprisingthe modifying agent into a stream of the liquid carrier, the injectionbeing carried out over a limited time so that a distinct test section ofthe stream contains the test sample, (b) passing the stream of liquidcarrier containing the test sample over a solid phase in a test chamber,the solid phase comprising the receptor, and (c) examining the stream ofliquid carrier leaving the test chamber to ascertain a variable whichreflects the interaction of the modifying agent and the receptor in thepresence of the liquid carrier.
 4. The method according to claims 1 or 2wherein modifying agent comprises a non-biological polymer.
 5. Themethod according to claim 2 wherein the library is a library ofreceptors.
 6. The method according to claim 2 wherein the library is alibrary of receptors, each of the members of the library comprising adifferent material selected from the group consisting of a fabric, asubstantially pore-free sheet of an organic polymer, a foodstuff, wood,concrete, natural or artificial stone, and a semiconductor.
 7. Themethod according to claim 2 wherein the library is a library ofreceptors, each of the members of the libraries comprising a same commonmaterial selected from the group consisting of a fabric, a substantiallypore-free sheet of an organic polymer, a foodstuff, wood, concrete,natural or artificial stone, and a semiconductor, wherein the samecommon material has been pretreated with a different non-biologicalpolymer.
 8. The method according to claim 2 wherein the library is alibrary of modifying agents.
 9. The method according to claim 2 whereinthe library is a library of modifying agents, each of the at least fourmembers of the library comprising a non-biological polymer.
 10. Themethod according to claim 2 wherein the library is a library ofmodifying agents, each of the at least four members of the librarycomprising a different non-biological polymer.
 11. The method accordingto claims 1, 2 or 3 wherein the liquid carrier is water or an aqueoussolution.
 12. The method according to claims 1, 2 or 3 wherein theliquid carrier is a non-aqueous polar solvent.
 13. The method accordingto claims 1, 2 or 3 wherein the liquid carrier is a non-polar solvent.14. The method according to claims 1, 2 or 3 wherein the receptorcomprises a fabric material.
 15. The method according to claims 1, 2 or3 wherein the receptor comprises a foodstuff material.
 16. The methodaccording to claims 1, 2 or 3 wherein the receptor comprises asemiconductor material.
 17. The method according to claims 2 or 3further comprising (d) using the results from the steps (c) of the testprocedures to select at least one member of the library for furthertesting; and (e) subjecting the member or members of the libraryselected in step (d) to further testing.
 18. The method according toclaims 2 or 3 wherein the at least four test procedures are conducted inparallel.
 19. The method according to claims 2 or 3 wherein in each ofthe test procedures, the efficiency of the test chamber is less than 50theoretical plates.
 20. The method according to claims 2 or 3 wherein ineach of the test procedures, the efficiency of the test chamber is lessthan 10 theoretical plates.
 21. The method according to claims 1, 2 or 3wherein in each of the test procedures, the test sample comprises aninitial quantity of the modifying agent, and at least 10% of the initialquantity of the modifying agent is irreversibly retained on the solidphase in the test chamber under test conditions of the procedures. 22.The method according to claims 1, 2 or 3 wherein in each of the testprocedures, the test sample comprises an initial quantity of themodifying agent, and 30% to 50% of the initial quantity of the modifyingagent is irreversibly retained on the solid phase in the test chamberunder test conditions of the procedures.
 23. The method according toclaims 2 or 3 wherein in each of the test procedures, the test samplecomprises an initial quantity of the modifying agent, a percentage ofthe initial quantity of the modifying agent is irreversibly retained onthe solid phase in the test chamber under test conditions of theprocedures, and the difference between the lowest and highestpercentages of the initial quantity of modifying agent retained in thetest chamber is at least 10% as compared between the at least four testprocedures.
 24. The method according to claims 1, 2 or 3 wherein in eachof the test procedures, the receptor is not saturated by the modifyingagent.
 25. The method according to claims 1, 2 or 3 wherein in each ofthe test procedures, a plot of time against concentration of themodifying agent in the stream of liquid carrier leaving the test chamberhas only a single peak, with the slope of the plot being positive at allpoints on one side of the peak and negative at all points after thepeak.
 26. The method according to claims 1, 2 or 3 wherein the receptorcomprises at least 50% by weight of particles having an aspect ratio ofat least 2 and at least one dimension which is greater than 100 micron.27. The method according to claims 1, 2 or 3 wherein in each of the testprocedures, the test sample comprises an initial quantity of themodifying agent and step (c) consists essentially of ascertaining theproportion of the initial quantity which, remains in the test section.28. The method according to claims 2 or 3 wherein in each of the testprocedures, step (c) comprises examining the stream of liquid carrierleaving the test chamber to ascertain a property of the modifying agentwhich remains in a distinct evaluation section of the streamcorresponding to the test section, and the test procedure furthercomprises (d) injecting a liquid reference sample into a stream of theliquid carrier, the composition of the second sample being substantiallyidentical to the composition of the test sample, and the injection beingcarried out over a limited time so that only a distinct referencesection of the stream contains the reference sample, (e) passing thestream of liquid carrier containing the reference sample through areference chamber which is free of any substance which interacts withthe modifying agent, (f) examining the stream of liquid carrier leavingthe reference chamber to ascertain a property of the modifying agentremaining in the stream, and (g) comparing the results obtained in steps(c) and (f) to evaluate the interaction between the receptor and themodifying agent.
 29. The method according to claim 28 wherein each ofsteps (c) and (f) comprises passing the stream of liquid carrier througha detector which measures a property which depends on the concentrationof the modifying agent, the measurement being carried out withoutremoving anything from the stream and at intervals which make itpossible to ascertain the amount of the modifying agent which remains inthe stream.
 30. The method according to claim 28 wherein in each of thetest procedures comprising steps (d) to (g), the first liquid streamcontaining the test section and the second liquid stream containing thereference section are obtained by injecting into the stream of liquidcarrier a liquid unit whose composition is the same as the compositionof the test and reference samples and whose size is equal to the sum ofthe sizes of the test and reference samples, the injection being carriedout over a limited time so that only a distinct section of the liquidstream contains the liquid unit, and splitting the liquid streamcontaining the liquid unit into a first sub-stream which passes throughthe test chamber and includes the test section and a second sub-streamwhich passes through the reference chamber and includes the referencesection.
 31. The method according to claim 30 wherein the liquid streamcontaining the liquid unit is split into the first and secondsub-streams by a flow-splitting junction.
 32. The method according toclaim 30 wherein the liquid stream containing the liquid unit is splitinto the first and second sub-streams by a switching valve.
 33. Themethod according to claim 28 wherein in each of the test procedurescomprising steps (d) to (g), the liquid stream containing the testsection and the liquid stream containing the reference section areobtained by injecting the liquid test sample into a first stream of theliquid carrier, the first stream being contained in a first line influid communication with the test chamber so that the first streamcontaining the test section passes through the test chamber, injectingthe reference sample into a second stream of the liquid carrier, thesecond stream being contained in a second line in fluid communicationwith the reference chamber so that the second stream containing thereference section passes through the reference chamber.
 34. An apparatusfor evaluating the interaction between a receptor comprising a selectedmaterial and a modifying agent, the apparatus comprising a test chamberhaving an inlet and an outlet and containing a solid phase comprisingthe receptor, the receptor comprising a material selected from the groupconsisting of a fabric, a substantially pore-free sheet of an organicpolymer, a foodstuff, wood, concrete, natural or artificial stone, and asemiconductor, a reservoir for containing a liquid carrier; a pump influid communication with the reservoir and in fluid communication withthe inlet of the test chamber, for continuously extracting a stream ofthe liquid carrier from the reservoir and passing the stream through thetest chamber; a sampling robot for sequentially injecting into thestream of the liquid carrier, before the stream passes through the testchamber, a plurality of liquid test samples, each sample containing aninitial quantity of one of the library of modifying agents and eachsample being injected over a limited time so that only a distinct testsection of the liquid stream contains the sample; and a detector influid communication with the outlet of the test chamber for examiningthe stream of liquid carrier leaving the test chamber and forascertaining the proportion of the initial quantity of the modifyingagent remaining therein.